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[Title] The adenomatous polyposis coli tumor suppressor and Wnt signaling in the regulation of apoptosis.

During normal development, Wnt signaling is required not only to induce cell proliferation and cell fate specification, but also to induce apoptotic cell death.

However in some malignant states triggered by APC loss, inappropriate activation of Wnt signaling promotes cell survival and inhibits cell death, indicating that the cellular response to APC loss and Wnt signaling is highly dependent on cell context.

This chapter summarizes our current understanding of the role of APC and Wnt signaling in the regulation of apoptosis, based upon studies from fly and mouse in vivo models, as well as cultured carcinoma cells.

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[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

It has been proposed that multiple rare variants in numerous genes collectively account for a substantial proportion of multifactorial inherited predisposition to a variety of diseases, including colorectal adenomas (CRA).

We have studied this hypothesis by sequencing the adenomatous polyposis coli (APC) gene in 691 unrelated North American patients with CRAs and 969 matched healthy controls.

Rare inherited nonsynonymous variants of APC were significantly overrepresented in patients who did not carry conventional pathogenic mutations in the APC or MutY homologue genes [non-familialadenomatous polyposis (FAP) non-MUTYH-associatedpolyposis (MAP) patients; 81 of 480, 16.9%] compared with patients with FAP or MAP (20 of 211, 9.5%, P = 0.0113), and this overrepresentation was highest in those non-FAP non-MAP patients with 11 to 99 CRAs (30 of 161, 18.6%, P = 0.0103).

APC shuttles between the nucleus and cytoplasm, however its role in the nucleus remains elusive.

We have found that nuclear APC specifically associates with transcriptionally active chromatin through structural elements located downstream to the region of frequent truncation mutations found in colorectal tumors.

We show that a recombinant APC fragment comprising such elements associates in vivo with euchromatin and preferentially binds in vitro to acetylated histone H3.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

The Adenomatous Polyposis Coli (APC) tumor suppressor is a multifunctional protein that is mutated in a majority of colon cancers.

The role of APC as an antagonist of the Wnt signaling pathway is well known and it is widely accepted that inappropriate activation of this pathway through loss of APC function contributes to the progression of colon cancers.

However, a body of evidence is growing to support the idea that APC plays non-traditional functions outside of the Wnt pathway with roles in cell migration, adhesion, chromosome segregation, spindle assembly, apoptosis, and neuronal differentiation.

This review highlights the research into alternate functions for APC beyond its role in Wnt signaling and discusses the possible contributions for these non-traditional functions of APC in tumor formation.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

The adenomatous polyposis coli (APC) tumour suppressor gene is mutated in the majority of colon cancers.

APC is a multi-domain protein whose distribution at different subcellular locations correlates with unique cellular processes.

Our laboratory has focused on the link between APC subcellular location and function, and has characterized pathways for the trafficking of APC both into and out of the nucleus.

Antibody specificity is an important factor in the determination of APC localization, and in this chapter we outline a strategy for the unambiguous detection of APC using a combination of biochemical and cell biology approaches.

Genotype-phenotype correlations were found in carriers of APC mutations but not in carriers of biallelic MYH mutations, except for a negative correlation with low number of polyps.

A distinctive characteristic of patients negative for APC and MYH mutations was a significantly (p<0.0001) older age at diagnosis compared to patients with APC mutations.

Moreover, the proportion of cases with an attenuated polyposis phenotype was higher (p = 0.0008) among patients negative for APC and MYH mutations than among carriers of APC or biallelic MYH mutations.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Novel de novo BRCA1 mutation in a woman with early onset breast cancer.

Mutation carriers usually have a family history of breast/ovarian cancer or early onset disease.

Rarely, germline mutations are found only in the probands but not in any family members.

Such de novo mutations have been reported in diseases such as hemophilia A, thalassaemia and familialadenomatous polyposis.

De novo mutations in the BRCA1 or BRCA2 genes are rare and the few reported have been in BRCA2.

Here, we describe de novo as well as novel mutation of the BRCA1 gene in a breast cancer patient.

METHODS: Blood DNA samples from a 30 year old Chinese woman with breast cancer and no family history of cancer was tested for a BRCA1/2 mutation by full gene sequencing and Multiple Ligation-dependent Probe Amplification (MLPA).

MLPA revealed a large deletion of exons 1 to 12 of BRCA1 in the proband.

MLPA performed on 5 family members: proband's mother and father (who were 1<sup>st</sup> degree relative- cousins), stepmother (mother's biological sister), 2 sisters (1, same parents; 1, same father and stepmother) found no similar deletion.

CONCLUSIONS: We report a novel de novo BRCA1 deletion mutation encompassing exons 1 - 12 in a Chinese breast cancer patient of early onset with no family history.

Identification of this large deletion confirms the importance of pursuing rearrangement testing if full gene sequencing fails to detect a point mutation or short insertion deletion.

The mutation found in this study is de novo.

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(PMID = 27963527.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[Publication-country] United States

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

: e20569 Background: Improvement of quality of life (QOL) is a major therapeutic goal for men with advanced prostate cancer (APC).

The PROSQOLI consists of a series of 9 linear analog self-assessment (LASA) scales that evaluate pain, fatigue, appetite, constipation and other symptoms, and overall well-being; it was designed and validated for use in patients with APC.

Here we evaluate the use of a computer-based version of the PROSQOLI in routine clinical practice for its ability to stimulate recognition of symptoms and for its impact on clinical decision-making.

METHODS: Consenting patients with APC completed a touch screen version of the PROSQOLI before seeing the doctor at visits to the outpatient clinic.

In phase I of the study physicians did not have access to this information; in phase II physicians were provided with results of the PROSQOLI and its changes from previous visits.

Rates of documentation did not differ between study phases.

Prostate cancer-specific symptoms were poorly documented in clinical notes; improved recording of symptoms might be facilitated by the use of a tool such as the electronic touch-screen PROSQOLI.

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(PMID = 27961125.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Evaluation of stool melting curve analysis of methylated CpG island promoters as an alternative for early noninvasive diagnosis of colorectal tumors.

: e15036 Background: Previous studies have shown that assessment of promoter hypermethylation of a limited number of genes in tumor biopsies may identify all colorectal tumors analyzed.

The aim of the present study was to assess the clinical usefulness of a panel of methylation biomarkers in stool DNA in the diagnosis of colorectal tumors using Methylation Curve (MC) analyses, a technique that simultaneously analyze all CpG residues within a promoter.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

: e22181 Background: I1307K is a missense APC variant with incomplete penetrance that has been found in 6% of Jewish Ashkenazi population and confers a two-fold increased risk to develop multiple adenomas and colorectal tumours.

It remains unknown whether the presence of this mutation modifies APC expression.

CONCLUSIONS: I1307K variant is not associated with allelic specific expression at the germline level.

I1307K overexpression is not selected for during tumor progression.

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(PMID = 27963596.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

The investigational ProCaM assay detects CpG island methylation within the promoter regions of three markers (GSTP1, RARß2, and APC) that are indicative of the presence of prostate cancer.

METHODS: Assay reproducibility: 8 operators from 4 external clinical laboratories tested a panel comprised of a negative panel member (NM2C5 cells) for the internal control (ß-Actin), a high positive and low positive panel members (LNCaP cells) for all 3 markers and ß-Actin.

The overall intersite %CV and SD values for Cts were = 9.2% and 1.49%, respectively.

The percent agreement with qualitative (positive/negative) outcome for High, Low, and Negative panel members was = 98% for GSTP1, RARß2, APC, and ß-Actin.

Using the result categories of negative and positive with identical cutoffs for GSTP1, RARß2, APC for samples with >5 ssDNA copies 98% concordance was observed for all 3 lots evaluated.

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(PMID = 27963156.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[Title] Effect of the I1307K polymorphism in APC confers a higher risk for polyp recurrence in Jewish Ashkenazi carriers.

Germline genetic analysis for the APC I1307K variant was performed using real-time PCR for DNA extracted from peripheral mononuclear cells.

Among Ashkenazi Jews, the I1307K variant was significantly more prevalent among persons with a personal or family history (1<sup>st</sup> degree) of CR neoplasia (p=0.01) as compared to Ashkenazi Jews with no family history.

The histopathological features of adenomas and cancers did not differ between carriers and non-carriers.

CONCLUSIONS: In the general population, the APC I1307K variant does not change the risk or prognosis of colorectal neoplasia in carriers and does not necessarily change their clinical practice.

Nevertheless, the variant, which is more prevalent among high risk individuals of Ashkenazi Jewish origin, is an important risk factor for the assessment of recurrence of neoplasia as it confers a higher risk for polyp recurrence in this population.

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(PMID = 27963171.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

: e11505 Background: We have previously shown that alkylating agent based chemotherapy regimens (AQT) could induce MIS in the PBMNF of BC patients in parallel to a decrease in the expression of the protein hMSH2 in these cells (Fonseca et al., 2005, Breast Cancer Res, 7, R28-32).

Blood (pfDNA and PBMNNF) and urine (ufDNA) were evaluated at time 0,3 and 6 months with 6 MIS markers (BAT40,BAT26, MR2,TP53 PCR15.1, APC and ALU).

CONCLUSIONS: We conclude that Chemotherapy as well as Fulvestran can induce MIS in normal and malignant cells and that in vitro these effects could be reproduced by treatment with M and prevented in normal cells by A.

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(PMID = 27964585.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[Publication-type] Journal Article

[Publication-country] United States

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Various pathogenesis have been given for the adenocarcinoma, like mutation in the E-catherin gene, amplification of COX-2, HGF/ SF, VEGF; deletion of FHIT, APC, p53 but none have provided a definite target for treatment.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Recently, we showed that triplet chemotherapy consisting of gemcitabine 800 mg/m<sup>2</sup> (10 mg/m<sup>2</sup>/min) followed by oxaliplatin 85 mg/m<sup>2</sup> and 48-hour infusion of 5-FU/LV 3,000 and 150 mg/m<sup>2</sup> Q 2 weeks, the GOFL regimen, is feasible and active for pts with APC.

Patients who did not experience disease progression (PD) after 6 cycles of GOFL would had CCRT consisting of weekly gemcitabine 400mg/m<sup>2</sup> plus 50.4Gy/28 fractions of radiation 4-6 weeks later.

After CCRT, pts were re-evaluated for surgical intervention and those with unresectable disease would continue GOFL until PD, unacceptable toxicity, patient's refusal or death.

Among the 34 (68%) with objective response or stable disease after 6 cycles of ICT, 27 (54%) who completed the assigned multimodality treatment are categorized as CCRT group; whiles 7 (14%) who either declined CCRT (in 5) or still on ICT (in 2) are categorized as non-CCRT group.

The median PFS and OS for the ITT population were 9.1 and 14.5 months, respectively.

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(PMID = 27962329.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

The CDX-1307 vaccine is composed of B11 fused with hCGβ, a tumor antigen correlated with advanced stage of disease and poor prognosis in a number of common epithelial cancers, but reported at variable rates of expression.

To date, a significant mixed response was seen in one patient with pancreatic cancer (id), while stable disease has been seen in 4 patients (2 with breast cancer = 25, 27 weeks and 2 with colorectal cancer = 9+ weeks).

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(PMID = 27962048.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] A prospective, randomized trial of chemotherapy with or without the low molecular weight heparin (LMWH) enoxaparin in patients (pts) with advanced pancreatic cancer (APC): Results of the CONKO 004 trial.

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(PMID = 27960826.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

: 2502 Background: The proton pump inhibitor omeprazole (Losec) is one of the most extensively prescribed medications worldwide and within its class, omeprazole is most frequently associated with drug interactions.

Plasma samples were obtained up to 55 hours after infusion and analyzed for irinotecan, and its metabolites SN-38, SN-38 glucuronide (SN-38G), NPC, and APC by reversed-phase high-performance liquid chromatography with fluorescence detection.

RESULTS: The mean AUCs of irinotecan and all metabolites were not significantly different between both courses (p>.151; see table).

The nadir ANC and WBC and the percentage decrease in ANC and WBC from baseline were not different between both courses (p>.529).

CONCLUSIONS: Omeprazole 40 mg did not alter the pharmacokinetics and toxicities of irinotecan.

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(PMID = 27961961.001).

[ISSN] 1527-7755

[Journal-full-title] Journal of clinical oncology : official journal of the American Society of Clinical Oncology

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Recruitment of adenomatous polyposis coli and beta-catenin to axin-puncta.

The adenomatous polyposis coli (APC) tumour suppressor is a multifunctional protein involved in the regulation of Wnt signalling and cytoskeletal dynamics.

Little is known about how APC controls these disparate functions.

In this study, we have used APC- and axin-fluorescent fusion proteins to examine the interactions between these proteins and show that the functionally distinct populations of APC are also spatially separate.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

On the other hand, recent epigenetic studies suggest the involvement of some tumor suppressor genes, including the adenomatous polyposis coli (APC) gene.

In the present study, we examined 10 infantile pure YSTs for mutation, allelic loss, promoter methylation, and protein expression status of the APC gene to evaluate whether the APC gene plays a significant role in the pathogenesis of infantile YSTs.

Loss of heterozygosity at 5q21, where the APC gene is localized, was detected in at least 3 (30%) of the 9 YSTs examined.

Immunohistochemically, 8 infantile YSTs did not express the APC protein, whereas 2 YSTs without showing APC methylation, as well as germ cells of normal infantile testes, expressed this protein in the cytoplasm.

These data indicate that inactivation of the APC gene, by allelic loss and/or promoter methylation, is related to the occurrence of infantile YSTs.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

AIMS: To determine whether the dissociation of tumour cells from neoplastic glands in colorectal carcinomas is caused by disruption of the wnt-signalling pathway and whether the adenomatous polyposis coli (APC) protein is implicated in this.

METHODS AND RESULTS: In a series of 99 clinically sporadic colorectal carcinomas, APC exon 15 mutations, loss of heterozygosity (LOH) and promoter methylation were found in 49, 20 and 23 cases, respectively.

Singly, these APC aberrations were not associated with the degree of tumour cell dissociation, but dissociation was higher for the cases with combined APC mutation and LOH.

Immunohistochemical beta-catenin translocation to the nucleus correlated with APC aberrations.

CONCLUSIONS: In colorectal carcinomas, wnt dysregulation relates to APC aberrations, but wnt dysregulation and APC aberrations are not strictly required for tumour cell dissociation, and additional and/or alternative factors must play a role.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

The mutation cluster region (MCR) of adenomatous polyposis coli (APC) is located within the central part of the open reading frame, overlapping with the region encoding the 20 amino acid repeats (20R) that are beta-catenin-binding sites.

Each mutation in the MCR leads to the synthesis of a truncated APC product expressed in a colorectal tumour.

The MCR extends from the 3' border of the first 20R coding region to approximately the middle of the third 20R coding region, reflecting both positive and negative selections of the N- and C-terminal halves of the APC protein in colon cancer cells, respectively.

In contrast, the second 20R escapes selection and can be either included or excluded from the truncated APC products found in colon cancer cells.

To specify the functional outcome of the selection of the mutations, we investigated the beta-catenin binding capacity of the first three 20R in N-terminal APC fragments.

Similarly, we also show that the tumour-associated truncations abolish the interaction of beta-catenin with the third 20R.

Thus, our data provide a functional definition of the MCR: the APC fragments typical of colon cancer are selected for the presence of a single functional 20R, the first one, and are therefore equivalent relative to beta-catenin binding.

Among them a recently discovered unique role of APC is in DNA repair.

Taken together with the transcriptional activation of APC gene by alkylating agents and modulation of BER activity, APC may play an important role in carcinogenesis and chemotherapy by determining whether cells with DNA damage survive or undergo apoptosis.

We identified Rdh5 as a retina-specific retinol dehydrogenase controlled by APC.

Microarray analyses of apc mutants and Rdh5 morphants revealed a profound overlap in the transcriptional profile of these embryos.

These findings support a model wherein Apc serves a dual role in regulating Wnt and retinoic acid signaling within the eye and suggest retinoic acid deficiency as an explanation for APC mutation-associated retinal defects such as congenital hypertrophy/hyperplasia of the retinal pigmented epithelium.

APC gene inactivation leads to dysfunction of beta-catenin protein degradation, and then activates Tcf/Lef and causes abnormal transcription of oncogenes, such as c-myc, c-jun and cyclin D1, finally leads to carcinogenesis.

This study was to investigate the correlation of methylation status of APC gene promoter 1A to protein expression of APC gene in breast cancer, and analyze the correlation of aberrant methylation of APC gene to clinicopathologic features of breast cancer.

CONCLUSION: Abnormal methylation of APC gene occurs in the progression of breast cancer, which is the main cause for the absence of APC protein expression, and the major mechanism of inactivation of APC gene.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Nuclear accumulation of the complex between beta-catenin and proteins of the T-cell factor (Tcf) family is a hallmark of many cancers.

Targeting this interaction for drug development is complicated by the fact that E-cadherin and adenomatous polyposis coli (APC) bind to overlapping sites on beta-catenin.

To identify selective beta-catenin binding hot spots of Tcf4, E-cadherin, and APC, array technology with peptides of up to 53 amino acids length was used.

We identified minimal binding motifs in the beta-catenin ligands and showed that most of the 15-mer and 20-mer repeats of APC did not interact, at least when non-phosphorylated, and defined a consensus binding motif also present in APC.

The method allowed us to locate a hydrophobic pocket that was relevant for the Tcf, but not the E-cadherin interaction, and would thus constitute an ideal drug target site.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

PURPOSE: To evaluate the impact of adjuvant chemotherapy on the outcome of osteosarcoma of the extremities, and to identify prognostic factors using the expression of adenomatous polyposis coli (APC), cadherin and β-catenin Wnt-signalling markers.

METHODS: The clinical, demographic, anatomic and pathological factors including a detailed analysis of the immunohistochemical expression of cadherin, β-catenin and APC were retrospectively examined in 97 patients with osteosarcoma of the extremities (metastatic and non-metastatic at diagnosis), treated with surgery and/or chemotherapy from 1985 to 2000.

Although both hypomorphic heterozygotes developed intestinal polyps, tumor multiplicities were much lower than that in Apc(Delta716) mice, heterozygotes of an Apc null allele.

Like in Apc(Delta716) mice, loss of the wild-type Apc allele was confirmed for all polyps examined in the Apc(neoR) and Apc(neoF) mice.

In the embryonic stem cells homozygous for these hypomorphic Apc alleles, the level of the APC protein was inversely correlated with both the beta-catenin accumulation and beta-catenin/T-cell factor transcriptional activity.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

We serendipitously identified a single nucleotide polymorphism (SNP), 8636C>A (rs1804197) in the 3'-untranslated region of the adenomatous polyposis coli (APC) gene to be associated with autism spectrum disorder (ASD).

In order to gain further evidence for the association between the APC locus and ASD, we genotyped four additional adjacent common SNPs (rs2229992, rs42427, rs459552, and rs465899) in the coding regions within the APC gene in a set of Swedish ASDs and controls.

One common haplotype TGAG was found to be associated with ASD after haplotype analysis using both Haploview v3.1.1 (P = 0.006) and COCAPHASE v2.403 (P = 0.030).

This result is the first to suggest that the genomic locus at APC is associated with ASD, and that the APC gene itself is a good predisposing candidate to be evaluated in future studies due to its important role in neuronal development and function.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

We report here that Wnt-7a, a ligand active in the canonical Wnt signaling pathway, induces dissociation of the adenomatous polyposis coli (APC) protein from the beta-catenin cytoplasmic complex and the interaction of APC with alpha7-nAChRs in hippocampal neurons.

Interestingly, Wnt-7a induces the relocalization of APC to membranes, clustering of APC in neurites, and coclustering of APC with different, presynaptic protein markers.

Wnt-7a also increases the number and size of coclusters of alpha7-nAChRs and APC in presynaptic terminals.

Together, these results demonstrate that stimulation through the canonical Wnt pathway regulates the presynaptic localization of APC and alpha7-nAChRs with APC serving as an intermediary in the alpha7-nAChR relocalization process.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Mutations in adenomatous polyposis coli (APC) gene have not been previously characterized among Romanian patients with colorectal cancer (CRC).

We initiate this study to detect the mutations in APC gene in blood and tumor samples collected from 16 patients (10 men and 6 women) and blood samples from 21 first and second degree relatives of the patients.

In the same time, we have searched for 5 bp deletions at codon 1061 of APC gene by PAGE and SSCP methods.

In one patient, was detected a deletion of exon 13th of APC gene both in DNA extracted from blood and tumor samples.

Multiple deletions (e.g. in exon 6, 12, and in 15L and 15W regions) in DNA extracted from the tumor sample were detected, but not in DNA probe obtained from blood cells.

Till now, no mutation affecting 1061 codon of APC gene was identified in the patients investigated in our study.

METHODS: We sequenced the entire open reading frame of the APC gene and tested for two common MYH mutations in a population-based series of patients with colorectal cancer and 5 to 99 adenomas.

Missense adenomatous polyposis coli alterations identified in this colorectal cancer multiple-polyp population were analyzed in a population-based series of patients with colorectal cancer and healthy control subjects.

CONCLUSIONS: Germline missense APC alterations observed in 33 percent of patients with multiple colorectal neoplasms seemed to play a limited role in colorectal cancer risk when independently assessed by a population-based, case-control analysis.

METHODOLOGY/PRINCIPAL FINDINGS: We now demonstrate that the 20-amino acid repeat region of APC (M3-APC) also interacts with topo IIalpha in colonic epithelial cells.

However, cells with a mutated topo IIalpha isoform and lacking topo IIbeta did not arrest, suggesting that the cellular consequence of M2- or M3-APC expression depends on functional topoisomerase II.

Both purified recombinant M2- and M3-APC significantly enhanced the activity of topo IIalpha.

Of note, although M3-APC can bind beta-catenin, the G2 arrest did not correlate with beta-catenin expression or activity, similar to what was seen with M2-APC.

More importantly, expression of either M2- or M3-APC also led to increased aneuploidy in cells with full-length endogenous APC but not in cells with truncated endogenous APC that includes the M2-APC region.

CONCLUSIONS/SIGNIFICANCE: Together, our data establish that the 20-amino acid repeat region of APC interacts with topo IIalpha to enhance its activity in vitro, and leads to G2 cell cycle accumulation and aneuploidy when expressed in cells containing full-length APC.

These findings provide an additional explanation for the aneuploidy associated with many colon cancers that possess truncated APC.

280, 6942-6949); however, the mechanism is not clear.

Using an in vivo LP-BER assay system, we now show that the LP-BER is higher in APC-/- cells than in APC+/+ cells.

In addition to pol-beta, the pull-down experiments showed that the full-length APC also interacted with flap endonuclease 1 (Fen-1).

To further characterize the interaction of APC with pol-beta and Fen-1, we performed a domain-mapping of APC and found that both pol-beta and Fen-1 interact with a 138-amino acids peptide from the APC at the DRI-domain.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

The adenomatous polyposis coli gene (APC) was initially identified through its link to colon cancer.

It is associated with the regulation of cell cycle progression, survival, and differentiation of normal tissues.

Recent studies have demonstrated that APC is also expressed in the adult brain at high levels.

In this study, we evaluated the expression of APC and its association with beta-catenin signaling pathway, following the induction of an excitotoxic lesion by kainic acid (KA) injection, which cause pyramidal cell degeneration.

APC was predominantly present in oligodendrocytes in the normal brain, but was specifically associated with activated astrocytes in the KA-treated brain.

The phospho-GSK3beta levels also showed similar spatiotemporal patterns while beta-catenin expression was reduced at 1 and then increasingly returned to normal levels at 3, 7 days PI.

For the first time, our data demonstrate the injury-induced astrocytic changes in the levels of APC, GSK3beta, and beta-catenin in vivo, which may actively be participate in cell adhesion and in the signaling pathway regulating cell survivals during brain insults.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

This research assessed the importance of the adenomatous polyposis coli (APC) tumor suppressor mutation in the ability of apigenin to induce cell cycle arrest using HT29-APC cells, which contain inducible wild-type APC under the metallothionein promoter.

Treatment with apigenin (0, 20, 40, 60, and 80 microM) for 48 h resulted in reduction in the cell number (P < 0.05) concurrent with flow cytometry results showing a dose-dependent accumulation of cells in the G2/M phase in both HT29-APC and HT29-GAL cells without ZnCl(2) treatment.

Flow cytometric analysis showed an increase (P < 0.05) in the percentage of cells in G2/M when HT29-APC cells were treated with 80 microM apigenin for 120 h.

This increase was not present in HT29-APC cells when treated with both 80 microM apigenin and 100 microM ZnCl(2) for 120 h.

Western blot analysis verified the induction of APC protein expression in ZnCl(2)-treated HT29-APC cells but not in ZnCl(2)-treated HT29-GAL cells.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

The majority of sporadic colorectal cancers are triggered by mutations in the adenomatous polyposis coli (APC) tumor suppressor gene, leading to the constitutive activation of the Wnt/beta-catenin signaling pathway and formation of adenomas.

Despite this common genetic basis, colorectal cancers are very heterogeneous in their degree of differentiation, growth rate, and malignancy potential.

This comparative approach resulted in the establishment of a conserved signature of 166 genes that were differentially expressed between adenomas and normal intestinal mucosa in both species.

Functional analyses of the conserved genes revealed a general increase in cell proliferation and the activation of the Wnt/beta-catenin signaling pathway.

Moreover, the conserved signature was able to resolve expression profiles from hereditarypolyposis patients carrying APC germline mutations from those with bi-allelic inactivation of the MYH gene, supporting the usefulness of such comparisons to discriminate among patients with distinct genetic defects.

To determine the relationship between APC and its binding partner EB1, we monitored EB1-green fluorescent protein and endogenous APC concomitantly in living cells.

Only a small fraction of EB1 colocalized with APC at any one time.

Depletion of EB1 did not change the growth-stabilizing effects of APC on MT plus ends.

In addition, APC remained bound to MTs stabilized with low nocodazole, whereas EB1 did not.

Thus, we demonstrate that the association of endogenous APC with MT ends correlates directly with their increased growth stability, that this can occur independently of its association with EB1, and that APC and EB1 can associate with MT plus ends by distinct mechanisms.

In contrast, wild-type APC located poorly at mitochondria.

The knock down of mutant APC(N1337) in SW480 tumor cells caused an increase in apoptosis and mitochondrial membrane permeability, and this correlated with reduced Bcl-2 protein levels in mitochondrial fractions.

Interestingly, the silencing of APC did not alter expression of beta-catenin or the apoptotic regulatory factors Bax, Bcl-xL, or survivin.

APC formed a complex with Bcl-2 in mitochondrial fractions, and this may contribute to the APC-dependent regulation of Bcl-2.

We propose that a subset of cancer mutations induce APC mitochondrial localization and that APC regulation of Bcl-2 at mitochondria may contribute to tumor cell survival.

[Title] Structural basis of the recognition of the SAMP motif of adenomatous polyposis coli by the Src-homology 3 domain.

The SH3 domain of DDEF1 associates with the SAMP motifs of the adenomatous polyposis coli (APC) tumor suppressor.

The SAMP motifs are indispensable for the normal function of APC in tumor suppression.

Here we present the structural basis of the interaction between the DDEF1-SH3 domain and the APC-SAMP motifs.

We determined the solution structures of the DDEF1-SH3 domain both in a free state and in a complex with APC-SAMP.

As the affinity of the interaction was not sufficiently high for the determination of the complex structure in solution by conventional methods, we utilized a fusion protein of the DDEF1-SH3 domain and APC-SAMP.

The structures revealed that the SAMP motif adopts a class II polyproline type II helix even though it does not contain the PxxP motif and that a characteristically large hydrophobic pocket of the SH3 domain confers high selectivity to the interaction.

Furthermore, investigation into the backbone dynamics of the free and bound systems by NMR spin relaxation experiments demonstrated that the DDEF1-SH3 domain exhibits high flexibility at the peptide recognition site in the absence of the ligand and that most residues of the APC-SAMP motif display extensive local motions even in the stable complex.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Mutations in the adenomatous polyposis coli (APC) gene result in uncontrolled proliferation of intestinal epithelial cells and are associated with the earliest stages of colorectal carcinogenesis.

Cyclooxygenase-2 (COX-2) is elevated in human colorectal cancers and plays an important role in colorectal tumorigenesis; however, the mechanisms by which APC mutations result in increased COX-2 expression remain unclear.

Both morpholino knockdown of C/EBP-beta in APC mutant zebrafish and silencing of C/EBP-beta using small interfering RNA in HT29 colon cancer cells robustly decrease COX-2 expression.

Our findings support a sequence of events in which mutations in APC result in impaired retinoic acid biosynthesis, elevated levels of C/EBP-beta, up-regulation of COX-2, increased prostaglandin E(2) accumulation, and activation of Wnt target genes.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] The adenomatous polyposis coliprotein is an essential regulator of radial glial polarity and construction of the cerebral cortex.

Using conditional gene targeting in mice, we demonstrate that adenomatous polyposis coli (APC) serves an essential function in the maintenance of polarized radial glial scaffold during brain development.

In the absence of APC, radial glial cells lose their polarity and responsiveness to the extracellular polarity maintenance cues, such as neuregulin-1.

Elimination of APC further leads to marked instability of the radial glial microtubule cytoskeleton.

[Title] Genetic enhancement of the Lis1+/- phenotype by a heterozygous mutation in the adenomatous polyposis coli gene.

Because dynactin, a dynein regulator, interacts with end-binding protein 1 (EB1) and beta-catenin, two known binding partners of the adenomatous polyposis coli (APC) protein, we looked for a genetic interaction between Lis1 and APC.

Mice with a heterozygous truncating mutation in APC (Min mutation) do not exhibit neuronal migration defects or develop hydrocephalus.

However, the presence of the APC mutation increases the migration deficit and the incidence of hydrocephalus in Lis1+/- animals.

Lis1 and dynein distribution is altered in cells derived from Min mice, and both Lis1 and dynein interact with the C terminus of APC in vitro.

Together, our findings point to a previously unknown interaction between APC and Lis1 during mammalian brain development.

APC is involved in normal intestinal development and acts to influence a variety of cellular processes.

Loss of APC function leads to intestinal neoplasia in both mice and humans.

APC influences expression of specific genes, including the c-Myc oncogene, which functions as a transcriptional activator.

Loss of APC function leads to alterations in c-Myc-regulated genes including ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis.

A single nucleotide polymorphism (SNP) in the ODC promoter affecting c-Myc-dependent expression has been associated with risk of colorectal and other cancers.

Pharmaceuticals that target structural features of the c-Myc promoter, and suppress expression of c-Myc and other genes regulated by similar promoter elements, are being developed as potential colorectal cancer chemotherapies.

APC and APC-dependent genes, such as c-Myc and ODC, may be useful as genetic markers of risk and as targets for chemoprevention and therapy for colorectal cancer.

The colonic and extracolonic phenotype of this syndrome is very heterogeneous.

We report the case of a young male patient with an aggressive MYH-associatedpolyposis phenotype.

When he was 39 years old, he developed three synchronous jejunal adenocarcinomas and a mesenteric desmoid tumor.

Based on this report, we believe that screening of the entire small bowel should be recommended in MYH-associatedpolyposis patients, especially in those with duodenal adenomas.

Similar to patients with familialadenomatous polyposis, desmoid tumors also may be part of the clinical spectrum of MYH-associatedpolyposis and may prove to be a significant clinical problem in patients submitted to prophylactic colectomy.

RESULTS: The positive rates of APC and E-cadherin in ESCC were lower than those in the normal group (69.6% vs. 98.0%, p < 0.01; 19.6% vs. 96.3%, p < 0.01).

In accordance with the following order, normal epithelia --> basal cell hyperplasia --> dysplasia --> ESCC, hypoexpression of APC proteins occurred in ESCC, abnormalities of beta-catenin and E-cadherin started to appear in dysplasia, and overexpression of Cyclin D1 emerged from basal cell hyperplasia.

From well to poorly differentiated ESCC, the expression of APC, E-cadherin and cyclin D1 were gradually reduced, while beta-catenin was increased.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Deficiency of Adenomatous Polyposis Coliprotein in sporadic colorectal adenomas and its associations with clinical phenotype and histology.

AIM: To evaluate the frequency of the loss of the Adenomatous Polyposis Coli (APC) protein and to compare the APC status with the characteristics of colorectal adenomas.

METHODS: Immunohistochemical analysis of the APC protein was performed on 118 adenomas and the results were compared with parameters of malignant potential, location of adenomas, macroscopic appearance and age of the patients.

RESULTS: A complete loss of the APC protein was found in 28 (24%) adenomas, while 90 (76%) were APC positive.

Statistical analysis revealed no difference between APC-positive and negative adenomas as to the histological type (P = 0.327) and grade of dysplasia (P = 0.494).

We found that even advanced adenomas did not differ in their APC status from the non-advanced tumors (P = 0.414).

Finally, no difference was found when the location (P = 0.157), macroscopic appearance (P = 0.571) and age of patients (P = 0.438) were analysed and compared between both APC positive and negative adenomas.

CONCLUSION: Most adenomas expressed full-length APC protein, suggesting that protein expression is not a reliable marker for assessment of APC gene mutation.

Complete loss of APC protein did not influence morphology, location, or appearance of adenomas, nor was it affected by the patient's age.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] [Expression of beta-catenin and adenomatous polyposis coliprotein and correlation between them in the development of mouse tooth germ].

OBJECTIVE: To examine the distributions of beta-catenin and adenomatous polyposis coli (APC) protein in the tooth germ, and obtain the messages of function of the two factors and the relationship between them.

METHODS: Mice were selected and cohabited with the ratio of female mice to male ones being 2:1, and Embryo day 0.5 was confirmed based on the finding of vaginal plug.

The distributions of beta-catenin and APC protein in the Embryos on day 13.5, 14.5, 15.5, 16.5, 17.5 were examined in the paraffin-embedded sections by immunohistochemistry methods.

During the bud stage, strong positive expression of APC protein was found in the oral epithelium and the dental lamina, but the expression displayed a down-regulation tendency.

There was negative correlation between beta-catenin and APC protein (P<0.01).

Several mouse models (APC580D, APCDelta716, APC1309, APCMin, APC1638T) have been established to investigate carcinogenesis caused by APC mutations.

APC has both nuclear localization signals and nuclear export signals in its molecule, suggesting its occasional nuclear localization and export of beta-catenin from the nucleus.

APC is highly expressed in the intestinal and colorectal epithelia and may be involved in homeostasis of the enterocyte renewal phenomena, in which proliferation, migration, differentiation, and apoptosis are highly regulated both temporally and spatially.

Through the many binding proteins mentioned, APC can exert multiple functions involved in epithelial homeostasis.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Wnt pathway signaling is crucial in many cancers and data indicate crosstalk with other key cancer pathways, however in urothelial carcinogenesis it has not been extensively studied.

We searched for mutations in adenomatous polyposis coli (APC), a key regulator of the pathway, and studied b-catenin expression and interactions with the expression of other markers of apoptosis, angiogenesis, and proliferation in patients with invasive urothelial cancer.

The mutation cluster region of APC was directly sequenced in 70 patients with muscle invasive disease who were treated with surgery and adjuvant chemotherapy.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Methylation of the human APC gene promoter is associated with several different types of cancers and has also been documented in some pre-cancerous tissues.

We have examined the methylation of APC gene promoters in human placenta and choriocarcinoma cells.

This revealed a general hypomethylation of the APC-1b promoter and a pattern with monoallelic methylation of the APC-1a promoter in full term placental tissue.

However, there was no evidence of a parent-of-origin effect, suggesting random post zygotic origin of methylation.

Increased methylation of this promoter was observed in all choriocarcinoma-derived trophoblast cell lines, suggesting a trophoblastic origin of placental APC methylation and implicating APC hypermethylation in the development of this group of gestational tumours.

Our demonstration of placental methylation of the APC-1a promoter represents the first observation of monoallelic methylation of this gene in early development, and provides further support for a role of canonical Wnt signalling in placental trophoblast invasiveness.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title]Adenomatous polyposis coli is differentially distributed in growth cones and modulates their steering.

Axonal steering reactions depend on the transformation of environmental information into internal, directed structures, which is achieved by differential modulation of the growth cone cytoskeleton; key elements are the microtubules, which are regulated in their dynamics by microtubule-associated proteins (MAPs).

We investigated a potential role of the MAPadenomatous polyposis coli (APC) for growing axons, employing embryonic visual system as a model system.

APC is concentrated in the distalmost (i.e., growing) region of retinal ganglion cell axons in vivo and in vitro.

Within the growth cone, APC is enriched in the central domain; it only partially colocalizes with microtubules.

When axons are induced to turn toward a cell or away from a substrate border, APC is present in the protruding and absent from the collapsing growth cone regions, thus indicating the future growth direction of the axon.

To assess the functional role of the differential distribution of APC in navigating growth cones, the protein was inactivated via micro-scale chromophore-assisted laser inactivation in one half of the growth cone.

If the N-terminal APC region (crucial for its oligomerization) is locally inactivated, the treated growth cone side collapses and the axon turns away.

In contrast, if the 20 aa repeats in the middle region of APC (which can negatively regulate its microtubule association) are inactivated, protrusions are formed and the growth cone turns toward.

Our data thus demonstrate a crucial role of APC for axon steering attributable to its multifunctional domain structure and differential distribution in the growth cone.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Microsatellite analysis of the adenomatous polyposis coli (APC) gene and immunoexpression of beta catenin in nephroblastoma: a study including 83 cases treated with preoperative chemotherapy.

AIMS: To determine whether microsatellite mutations of the adenomatous polyposis coli (APC) gene have pathological or prognostic significance in nephroblastomas and to correlate APC alterations with beta catenin immunoexpression.

Polymerase chain reaction using four APC microsatellite markers-D5S210, D5S299, D5S82, and D5S346-was performed and the products analysed.

Although there was a significant correlation between the results for individual markers and the clinicopathological data, the overall results do not support a prognostic role for APC in nephroblastoma.

CONCLUSION: Microsatellite analysis of APC and immunoexpression of beta catenin did not provide significant pathological or prognostic information in this cohort of nephroblastomas.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Is prophylactic colectomy indicated in patients with MYH-associatedpolyposis?

OBJECTIVES: The MYH gene has recently been associated with multiple colorectal tumours.

It participates in the DNA base-excision-repair, avoiding mutations in other genes, namely the APC and Ki-ras.

Recently, biallelic MYH mutations have been described in patients with attenuated polyposis and in 7.5% with classic polyposis and no detectable APC mutation.

The aim of this study was to analyse the incidence of germ-line MYH mutations in selected Portuguese families recorded in a hereditary tumour registry and to evaluate the risk of colorectal cancer in this syndrome.

RESULTS: Biallelic germline mutations in MYH were identified in 9 of the attenuated polyposis and in one of the classic polyposis patients.

The mean age at the clinical diagnosis was 50.6 years (from 35 to 69 years); six were men and four women.

Five patients belonged to families with affected siblings; three showed evidence for vertical transmission and two had no evidence for familial transmission of the disease.

Eight patients had associated malignant degeneration: three T3N+, four T3N0 and one T1N+.

CONCLUSION: A large frequency of biallelic MYH mutations (69%) was found in APC mutation negative patients belonging to families with attenuated polyposis; the highest percentage was observed in families presenting evidence for horizontal transmission of the disease.

The high percentage of degeneration found in these patients suggests that colonoscopy with polypectomies is not sufficient and prophylactic colectomy is recommended.

The identification of MYH associatedpolyposis is important to evaluate the level of risk, particularly for the siblings.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Purification and characterization of a high specificity polyclonal antibody to the adenomatous polyposis coli tumour suppressor protein.

Recombinant proteins, commonly expressed in fusion with an affinity tag to facilitate purification, are often used as immunogens for polyclonal antibody production.

Careful immunopurification of the antibody product is often the key to obtaining a high-specificity polyclonal antibody against the protein domain of interest.

This study describes the purification and characterization of such an antibody directed against the adenomatous polyposis coli (APC) tumour suppressor.

This antibody was then characterized by immunoprecipitation, proteomic analyses and immunofluorescence staining and shown to be a valuable reagent for the study of APC biology.

Using this antibody we successfully isolated and identified APC, using MS/MS, from transfected cell lines.

A novel phosphorylation site on APC was identified at ser 1436.

Similar strategies involving multiple immuno-affinity steps coupled with surface plasmon resonance (SPR), immunoprecipitation proteomic and immunofluorescence analyses should be generally applicable for the purification and characterization of other polyclonal antibodies.

[Title] Tumor-associated NH2-terminal fragments are the most stable part of the adenomatous polyposis coliprotein and can be regulated by interactions with COOH-terminal domains.

APC is a large, multifunctional protein involved in cell migration, proliferation, and differentiation.

Dominant effects that have been attributed to the NH2-terminal fragments of APC expressed in tumors may result from loss of functions due to lack of COOH-terminal regions or gain of functions due to fewer regulatory interactions.

Resolving this issue and determining how structural changes contribute to the multiple functions of the APC protein requires knowledge about the structural organization of the APC molecule.

We discovered that the NH2-terminal region of APC was most resistant to proteolytic degradation, whereas middle and COOH-terminal regions were significantly more sensitive.

Binding of APC to microtubules protected COOH-terminal regions of APC against proteolysis, consistent with the idea that this region of the molecule becomes ordered when bound to microtubules.

Furthermore, interactions between the NH2- and COOH-terminal domains of APC were identified in vitro and in vivo, suggesting that NH2-terminal fragments of APC may be regulated by interactions with COOH-terminal domains.

Indeed, expressing COOH-terminal APC fragments in tumor cells resulted in changes in the protein interactions of endogenous NH2-terminal fragments in these cells.

Thus, the dominant function of NH2-terminal APC fragments found in tumor cells could be explained by loss of this regulation in tumors where COOH-terminal domains are missing.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Adenomatous polyposis coli (APC) protein is a large tumor suppressor that is truncated in most colorectal cancers.

The carboxyl-terminal third of APC protein mediates direct interactions with microtubules and the microtubule plus-end tracking protein EB1.

In addition, APC has been localized to actin-rich regions of cells, but the mechanism and functional significance of this localization have remained unclear.

Here we show that purified carboxyl-terminal basic domain of human APC protein (APC-basic) bound directly to and bundled actin filaments and associated with actin stress fibers in microinjected cells.

Actin filaments and microtubules competed for binding to APC-basic, but APC-basic also could cross-link actin filaments and microtubules at specific concentrations, suggesting a possible role in cytoskeletal cross-talk.

APC interactions with actin in vitro were inhibited by its ligand EB1, and co-microinjection of EB1 prevented APC association with stress fibers.

Point mutations in EB1 that disrupted APC binding relieved the inhibition in vitro and restored APC localization to stress fibers in vivo, demonstrating that EB1-APC regulation is direct.

Because tumor formation and metastasis involve coordinated changes in the actin and microtubule cytoskeletons, this novel function for APC and its regulation by EB1 may have direct implications for understanding the molecular basis of tumor suppression.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

Most colorectal cancers have mutations of the adenomatous polyposis coli (APC) gene or the beta-catenin gene that stabilize beta-catenin and activate beta-catenin target genes, leading ultimately to cancer.

The molecular mechanisms of APC function in beta-catenin degradation are not completely known.

APC binds beta-catenin and is involved in the Axin complex, suggesting that APC regulates beta-catenin phosphorylation.

Some evidence also suggests that APC regulates beta-catenin nuclear export.

Here, we examine the effects of APC mutations on beta-catenin phosphorylation, ubiquitination, and degradation in the colon cancer cell lines SW480, DLD-1, and HT29, each of which contains a different APC truncation.

Although the current models suggest that beta-catenin phosphorylation should be inhibited by APC mutations, we detected significant beta-catenin phosphorylation in these cells.

However, beta-catenin ubiquitination and degradation were inhibited in SW480 but not in DLD-1 and HT29 cells.

The ubiquitination ofbeta-catenin in SW480 cells can be rescued by exogenous expression of APC.

The APC domains required for beta-catenin ubiquitination were analyzed.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] Identification of a link between the SAMP repeats of adenomatous polyposis coli tumor suppressor and the Src homology 3 domain of DDEF.

The adenomatous polyposis coli (APC) tumor suppressor protein is a multifunctional protein with a well characterized role in the Wnt signal transduction pathway and in cytoskeletal regulation.

The SAMP repeats region of APC, an Axin-binding site, is known to be important for tumor suppression and for the developmental function of APC.

We performed a yeast two-hybrid screening using the first SAMP motif-containing region of Xenopus APC as bait and obtained several SAMP binding candidates including DDEF2 (development and differentiation enhancing factor 2), which is an ADP-ribosylation factor (Arf) GTPase-activating protein (GAP (ArfGAP)) involved in the regulation of focal adhesions.

In vitro and in cells the Src homology 3 (SH3) domain of DDEF2 and its close homolog, DDEF1, are associated with the SAMP motif of APC competitively with Axin1.

When fluorescent protein-tagged APC and DDEF are expressed in Xenopus A6 cells, co-localization at microtubule ends is observed.

Overexpression and RNA interference experiments indicate that APC and DDEFs cooperatively regulate the distributions of microtubules and focal adhesions.

Our findings reveal that the SAMP motif of APC specifically binds to the SH3 domains of DDEFs, providing new insights into the functions of APC in cell migration.

[Source] The source of this record is MEDLINE®, a database of the U.S. National Library of Medicine.

[Title] [Spatial-temporal distribution of glycogen synthase kinase 3beta and adenomatous polyposis coliprotein are involved in the injury and repair of airway epithelial cells induced by scratching].

To investigate the roles of glycogen synthase kinase 3beta (GSK3beta) and adenomatous polyposis coli (APC) protein in wound repair of airway epithelial cells (AECs), we established a wound model of airway epithelium in vitro.

(2) The localizations of APC protein was observed by using immunofluorescence technique;.

(3) Immunoprecipitation was used to investigate the relationship between APC protein and GSK3beta during the repair of 16HBE cells.

(2) Results of immunofluorescence study showed that APC protein clustered with tubulin in the region of the migrating leading cells 6 h after scratching, which was dissimilar with that in the cells 0 h after scratching;.

(3) GSK3beta and APC protein were immunoprecipitated and analysed on SDS-PAGE.

We found that GSK3beta and APC protein were precipitated, indicating that the two proteins existed in a complex.

After scratching, dissociation of the two proteins occurred.

Taken together, we conclude that scratching caused a decrease in phosphorylation of GSK3beta, and that reduced phosphorylation of GSK3beta promoted APC protein to bind to the plus ends of microtubules and stabilize the growing ends.

These observations suggest that APC protein and GSK3beta may synergistically play an important role in the repair of airway epithelium.